Cigarette smoking, the leading cause of preventable death in the United States, almost universally begins in adolescence. Smokers in this especially vulnerable age group are often interested in quitting, but are rarely successful when making quit attempts on their own. In light of this, and given the considerable health benefit of quitting smoking at a young age, evidence-based treatments for adolescent smoking cessation are critically needed. Surprisingly little research has addressed this need, and almost all of it has focused on psychosocial approaches, yielding generally small treatment effect sizes. Pharmacotherapy, while well established as a cessation treatment in adult smokers, has been the focus of only 6 controlled trials in adolescent smokers. These trials of nicotine replacement therapy and bupropion SR have produced mixed but generally encouraging results. Varenicline, a 42 nicotinic acetylcholine receptor partial agonist, has demonstrated superior cessation efficacy in adults across several randomized trials when compared to placebo, nicotine replacement therapy, and bupropion SR. Given its striking efficacy as an adult smoking cessation treatment, varenicline is a strong candidate for evaluation in adolescent smokers. Guided by dosing recommendations from an adolescent pharmacokinetic study and feasibility/safety information from an adolescent pilot cessation trial, a randomized, double blind placebo-controlled trial of varenicline for adolescent smoking cessation is proposed. Participants will be randomized to receive varenicline or placebo for 12 weeks, with multiple post-treatment follow-up visits through 6 months. Weekly psychiatric & medical visits, including detailed, rigorous safety/tolerability assessment, will be conducted throughout active treatment. All participants will concurrently participate in a contingency management intervention, designed to enhance study retention. The primary efficacy hypothesis is that participants receiving varenicline, compared with those receiving placebo, will demonstrate greater biologically confirmed 7-day point prevalence abstinence at the end of treatment. We further hypothesize adequate safety and tolerability, compared with placebo, in the frequency of treatment-emergent adverse events. The proposed study will fill a critical evidence gap, and has the potential to significantly advance adolescent smoking cessation treatment. Whether findings are positive, null, or negative, this will be an important contribution to the literature and will have considerale clinical and public health impact. PUBLIC HEALTH RELEVANCE: Cigarette smoking in adolescence is a serious problem with significant health consequences. Adolescent smokers have a hard time quitting cigarettes, and we need to develop effective treatments to help them. Varenicline, the most effective medication to help adults quit smoking, has not been tested in adolescents. Thus, the proposed study will investigate varenicline to help adolescents quit smoking.